Down-regulation of dendritic spine and glutamic acid decarboxylase 67 expressions in the reelin haploinsufficient heterozygous reeler mouse
Down-regulation of dendritic spine and glutamic acid decarboxylase 67 expressions in the reelin haploinsufficient heterozygous reeler mouse
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DOI：
10.1073/pnas.051614698
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发表时间：
2001-03-13
影响因子：
11.1
通讯作者：
Costa, E
中科院分区：
文献类型：
--
作者：
Liu, WS;Pesold, C;Costa, E
杂合reeler小鼠（HRM）单倍型reelin不足表达约50%的野生型小鼠的脑reelin含量，但表型不同于野生型小鼠和纯合reeler小鼠。它们表现出：（i）在额顶叶皮质（FPC）的一些但不是每个皮质层中谷氨酸脱羧酶67（GAD（67））阳性神经元的下调，（ii）由于神经元发育不全，神经元堆积密度增加和皮质厚度减少，（iii）运动FPC第III层锥体神经元的基底和顶端树突分支上树突棘表达密度减少，和（iv）海马CA1锥体神经元的基底树突分支上表达的树突棘的类似减少。为了确定在HRM中观察到的GAD（67）下调缺陷是否是神经元发育不全和树突棘密度降低的原因，我们研究了杂合GAD（67）敲除小鼠（HG（67）M）。这些小鼠在FPC中表现出GAD（67）mRNA表达下调（约50%），但它们表达正常量的reelin，并且没有神经元发育不全或树突棘表达下调。这些研究结果，再加上电子显微镜观察，reelin与整合素受体共定位的树突棘，表明reelin可能是一个因素，在动态表达的皮质树突棘也许通过促进整合素受体集群。这些发现是有趣的，因为HRM表现出的脑神经化学和神经解剖学表型特征在几个方面与精神病患者死后大脑中发现的相似。
Heterozygous reeler mice (HRM) haploinsufficient for reelin express approximate to 50% of the brain reelin content of wild-type mice, but are phenotypically different from both wild-type mice and homozygous reeler mice. They exhibit, (i) a down-regulation of glutamic acid decarboxylase 67 (GAD(67))-positive neurons in some but not every cortical layer of frontoparietal cortex (FPC), (ii) an increase of neuronal packing density and a decrease of cortical thickness because of neuropil hypoplasia, (iii) a decrease of dendritic spine expression density on basal and apical dendritic branches of motor FPC layer III pyramidal neurons, and (iv) a similar decrease in dendritic spines expressed on the basal dendrite branches of CA1 pyramidal neurons of the hippocampus. To establish whether the defect of GAD(67) down-regulation observed in HRM is responsible for neuropil hypoplasia and decreased dendritic spine density, we studied heterozygous GAD(67) knockout mice (HG(67)M). These mice exhibited a down-regulation of GAD(67) mRNA expression in FPC (about 50%), but they expressed normal amounts of reelin and had no neuropil hypoplasia or down-regulation of dendritic spine expression. These findings, coupled with electron-microscopic observations that reelin colocalizes with integrin receptors on dendritic spines, suggest that reelin may be a factor in the dynamic expression of cortical dendritic spines perhaps by promoting integrin receptor clustering. These findings are interesting because the brain neurochemical and neuroanatomical phenotypic traits exhibited by the HRM are in several ways similar to those found in postmortem brains of psychotic patients.